Ultra low dose doxepin and methods of using the same to treat sleep disorders

ABSTRACT

The invention relates to doxepin, pharmaceutically acceptable salts and prodrugs of doxepin; compositions containing the same, and the use of any of the aforementioned for the treatment of sleep disorders.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority to U.S. Provisional Application No.60/854,399 filed on Oct. 25, 2006 entitled ULTRA LOW DOSE DOXEPIN ANDMETHODS OF USING THE SAME TO TREAT SLEEP DISORDERS; U.S. ProvisionalApplication No. 60/873,056, filed on Dec. 6, 2006, entitled COMBINATIONTHERAPY USING LOW-DOSE DOXEPIN FOR THE IMPROVEMENT OF SLEEP; and U.S.Provisional Application No. 60/910,586, filed on Apr. 6, 2007, entitledCOMBINATION THERAPY USING LOW-DOSE DOXEPIN FOR THE IMPROVEMENT OF SLEEP;each of which applications is incorporated herein by reference in itsentirety.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The invention relates to ultra low doses of doxepin, as well aspharmaceutically acceptable salts and prodrugs of the same; compositionscontaining the same, and the use of any of the aforementioned for thetreatment of sleep disorders.

2. Description of the Related Art

Sleep is essential for health and quality of life. Insomnia is asubjective complaint of dissatisfaction with the quantity, quality ortiming of sleep. Insomnia is estimated to occur in approximately 12% to25% of the general population, although this is probably anunderestimate as there is evidence that many adults do not report theirsleep problems to a health care professional.

One study has found that fewer than 15% of those who suffer frominsomnia are treated with prescription medications. Medications commonlyused to treat insomnia include sedative antidepressants, antihistamines,benzodiazepines, and non-benzodiazepine hypnotics. Various side effectsare associated with the commonly used medications. For example, a sideeffect of some hypnotics is to reduce slow wave sleep. Other sideeffects of concern are possible daytime residual effects related tosedation, rebound insomnia, and minor side effects specific to each drugclass. Tolerance to beneficial effects on sleep is thought to occur withantihistamines and benzodiazepine and non-benzodiazepine hypnotics.

Until the arrival of the non-benzodiazepine hypnotics in the mid ‘90’s,benzodiazepines were the most common drugs used for the pharmacologicalmanagement of insomnia. These drugs work by binding to and activatingsites on the GABA-A receptor complex. Short, intermediate andlong-acting benzodiazepines such as triazolam, temazepam and flurazepamwere all commonly prescribed for this indication. While these agentshave proven to be efficacious and relatively safe, benzodiazepines areassociated with a multitude of adverse effects, including residualdaytime sedation (“hangover”), amnesia, memory loss and respiratorydepression. Rebound insomnia has also been associated withbenzodiazepines. Tolerance to the hypnotic effects of thebenzodiazepines is common and abrupt discontinuation can result inwithdrawal symptoms such as agitation, perceptual changes, confusion,disorientation and insomnia.

Most recently non-benzodiazepine hypnotics have become the primary classof medications for the treatment of insomnia. The leading approvednon-benzodiazepine insomnia medications, eszopiclone, zolpidem, andzaleplon, also work by binding to and activating the GABA-A receptors,but they are more selective in their binding than the benzodiazepines.All these drugs approved for the treatment of insomnia that act via theGABA-A receptor, including benzodiazepine and non-benzodiazepinehypnotics, have a potential for addiction and abuse and are classifiedas Schedule IV controlled substances by the U.S. Drug EnforcementAdministration. As a result, many physicians are reluctant to prescribe,and patients are reluctant to take, these drugs for chronic use intreating insomnia. The prescribing of a Schedule IV controlled substancebrings scrutiny from the Drug Enforcement Administration and otherregulatory bodies, and requires registration and administrative controlsin physicians' offices. Therefore, it is desirable to have apharmacological agent for the treatment of insomnia which is moreeffective and/or has fewer side effects that those currently used.

Recently a new hypnotic with a mode of action different from otherhypnotics has been introduced. Ramelteon is a melatonin receptor agonistwith high affinity for melatonin MT1 and MT2 receptors. It is indicatedfor sleep onset insomnia but it has not been shown to produce a sleepmaintenance benefit. It does not affect the GABA-A receptor complex, isnot addicting and is not scheduled.

The sedative antidepressants account for a large percentage of the totalprescriptions written for insomnia. The National Disease and TherapeuticIndex estimates that more than 60% of the 13 million annual trazodoneprescriptions are written for the treatment of insomnia, even thoughtrazodone is not indicated for that usage and has never been promotedfor that condition. Even though there are very limited data to supportthe use of trazodone for insomnia and it is associated with undesirableside effects, trazodone is often prescribed because it is anon-scheduled agent, meaning non-addictive, unlike the benzodiazepinesand other GABA-receptor agonists which are approved for the treatment ofinsomnia.

SUMMARY OF THE INVENTION

Some embodiments relate to methods for treating insomnia. In someembodiments, the methods for treating insomnia can include administeringto a patient doxepin, a pharmaceutically acceptable salt thereof, or aprodrug thereof in a daily dosage ranging from about 0.0001 to about0.49 milligrams. In some embodiments, the pharmaceutically acceptablesalt of doxepin can be the hydrochloride salt thereof. In someembodiments, the prodrug of doxepin can be a prodrug ester. In someembodiments, the daily dosage can be about 0.001 to about 0.1milligrams. In some embodiments, the daily dosage can be about 0.01 toabout 0.099 milligrams. In some embodiments, the methods can be fortreating a chronic insomnia or a non-chronic insomnia. In someembodiments, the non-chronic insomnia can be a transient or a short terminsomnia. In some embodiments, the insomnia can be onset insomnia ormaintenance insomnia. In some embodiments, the methods can be used wherethe patient is not suffering from depression. In some embodiments, themethods can be used where the patient is suffering from depression. Insome embodiments, the methods for treating insomnia can further includeadministering at least one of ramelteon, eszopiclone, zolpidem tartrate,or zaleplon. In some embodiments, the methods can further includeadministering at least one additional sleep medication. In someembodiments, the at least one additional sleep medication can be a 5-HT2antagonist, ketanserin, a H3 agonist, an orexin antagonist, anoradrenergic antagonist, a galanin agonist, a CRH antagonist,Gaboxadol, other GABA-A direct antagonists, a GABA reuptake inhibitor,tiagabine, a growth hormone, a growth hormone agonist, estrogen, anestrogen agonist, or a melatonin agonist. Other examples of medicationsand substances that can be used in combination with ultra low doses asdescribed herein can be found in U.S. Provisional Application No.60/873,056, filed on Dec. 6, 2006, entitled COMBINATION THERAPY USINGLOW-DOSE DOXEPIN FOR THE IMPROVEMENT OF SLEEP; and U.S. ProvisionalApplication No. 60/910,586, filed on Apr. 6, 2007, entitled COMBINATIONTHERAPY USING LOW-DOSE DOXEPIN FOR THE IMPROVEMENT OF SLEEP; each ofwhich applications is incorporated herein by reference in its entirety.

Other embodiments relate to compositions including doxepin, apharmaceutically acceptable salt thereof, or a prodrug of doxepin. Insome embodiments, the compositions can include doxepin, apharmaceutically acceptable salt thereof, or a prodrug of doxepin in adosage of about 0.0001 milligrams to about 0.49 milligrams. In someembodiments, the compositions further include a pharmaceuticallyacceptable carrier. In some embodiments, the pharmaceutically acceptablesalt of doxepin can be the hydrochloride salt thereof. In someembodiments, the prodrug can be an ester. In some embodiments, thecompositions can be in a form suitable for oral or nasal administration.In some embodiments, the compositions further include at least one oframelteon, eszopiclone, zolpidem tartrate, or zaleplon. In someembodiments, the compositions further include at least one additionalsleep medication. In some embodiments, the at least one additional sleepmedication can be a 5-HT2 antagonist, ketanserin, a H3 agonist, anorexin antagonist, a noradrenergic antagonist, a galanin agonist, a CRHantagonist, Gaboxadol, other GABA-A direct antagonists, a GABA reuptakeinhibitor, tiagabine, a growth hormone, a growth hormone agonist,estrogen, an estrogen agonist, or a melatonin agonist. Other examples ofmedications and substances that can be used in combination with ultralow doses as described herein can be found in U.S. ProvisionalApplication No. 60/873,056, filed on Dec. 6, 2006, entitled COMBINATIONTHERAPY USING LOW-DOSE DOXEPIN FOR THE IMPROVEMENT OF SLEEP; and U.S.Provisional Application No. 60/910,586, filed on Apr. 6, 2007, entitledCOMBINATION THERAPY USING LOW-DOSE DOXEPIN FOR THE IMPROVEMENT OF SLEEP;each of which applications is incorporated herein by reference in itsentirety.

Other embodiments relate to methods of shortening the time required toachieve a maximum plasma concentration of doxepin in a patient receivingdoxepin therapy. In some embodiments, the methods of shortening the timerequired to achieve a maximum plasma concentration of doxepin in apatient receiving doxepin therapy includes administering to the patientabout 0.0001 milligrams to about 0.49 milligrams of doxepin in apharmaceutical composition without food.

Other embodiments relate to methods of shortening the time required toachieve sleep onset. In some embodiments, the methods of shortening thetime required to achieve sleep onset include administering to thepatient about 0.0001 milligrams to about 0.49 milligrams of doxepin in apharmaceutical composition without food.

Other embodiments relate to methods of treating a sleep disorder. Insome embodiments, the methods of treating a sleep disorder includeproviding a patient with about 0.0001 milligrams to about 0.49milligrams of doxepin and providing the patient with instructions totake the doxepin without food.

Other embodiments relate to methods of increasing the oralbioavailability of doxepin. In some embodiments, the methods ofincreasing the oral bioavailability of doxepin include administeringwith food to a patient a pharmaceutical oral dosage form of doxepin inan amount of about 0.0001 milligrams to about 0.49 milligrams. In someembodiments, the methods of increasing the oral bioavailability ofdoxepin to a patient receiving doxepin therapy, include administering tothe patient with food a pharmaceutical oral dosage form of doxepincomprising about 0.0001 milligrams to about 0.49 milligrams of doxepin,wherein the administration results in an AUC_(0-∞) that is greater thanthat achieved by the administration of the same amount of doxepinwithout food.

Other embodiments relate to methods of treating depression or anxiety.In some embodiments, the methods of treating depression or anxietyinclude administering about 0.0001 milligrams to about 0.49 milligramsof doxepin with food. In some embodiments, the methods of treatingdepression or anxiety, include providing a patient with doxepin in anamount of about 0.0001 milligrams to about 0.49 milligrams and providingthe patient with instructions to take the doxepin with food. In someembodiments, the methods of treating depression or anxiety includeproviding a patient with doxepin in an amount of about 0.0001 milligramsto about 0.49 milligrams and providing the patient with informationregarding a doxepin food effect.

Other embodiments relate to methods of decreasing the oralbioavailability of doxepin. In some embodiments, the methods ofdecreasing the oral bioavailability of doxepin include administering toa patient a pharmaceutical oral dosage form of doxepin comprisingdoxepin in an amount of about 0.0001 milligrams to about 0.49 milligramswithout food. In some embodiments, the methods of decreasing the oralbioavailability of doxepin to a patient receiving doxepin therapy,include administering to the patient without food a pharmaceutical oraldosage form of doxepin including doxepin in an amount of about 0.0001milligrams to about 0.49 milligrams, wherein the administration resultsin an AUC_(0-∞) that is less than that achieved by the administration ofthe same amount of doxepin with food.

Other embodiments relate to methods of alleviating a doxepin foodeffect. In some embodiments, the methods of alleviating a doxepin foodeffect include administering about 0.0001 milligrams to about 0.49milligrams of doxepin to a patient in need thereof, wherein the patientis in a non-fasted state. In some embodiments, the methods ofalleviating a doxepin food effect include administering about 0.0001milligrams to about 0.49 milligrams of doxepin to a patient in needthereof, wherein the patient is in a fasted state.

Other embodiments relate to methods of minimizing side effectsassociated with a doxepin therapy. In some embodiments, the methods ofminimizing side effects associated with a doxepin therapy includeadministering about 0.0001 milligrams to about 0.49 milligrams ofdoxepin to a patient with food.

Other embodiments relate to methods for improving the consistency ofpharmacokinetics associated with doxepin therapy. In some embodiments ofthe methods for improving the consistency of pharmacokinetics associatedwith doxepin therapy, a patient receives multiple doxepin dosages overmultiple days, comprising administering about 0.0001 milligrams to about0.49 milligrams of doxepin to the patient in a fixed temporalrelationship to food intake by the patient.

Other embodiments relate to products including doxepin. In someembodiments, the products include doxepin in an amount of about 0.0001milligrams to about 0.49 milligrams and written instructions associatedtherewith to take the doxepin without food. In some embodiments, theproducts include doxepin in an amount of about 0.0001 milligrams toabout 0.49 milligrams and written instructions associated therewith totake the doxepin with food. In some embodiments the products includedoxepin in an amount of about 0.0001 milligrams to about 0.49 milligramsand written information associated therewith regarding a doxepin foodeffect.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT

Generally, embodiments of the present invention relate to ultra lowdoses of doxepin, pharmaceutically acceptable salts and prodrugs ofdoxepin, pharmaceutical compositions that include any the mentionedsubstances in ultra low doses, and use of the substances andcompositions to treat an individual having a sleep disorder. Forexample, the sleep disorder can be insomnia. Also, some embodimentsrelate to methods of improving the pharmacokinetics of ultra low dosedoxepin in a patient.

Surprisingly, the ultra low doses of doxepin, salts and prodrugs of thesame are effective for treating sleep disorders. The ultra low doses ofthese substances have little or no abuse potential, have a rapid onsetof action, and very minimal side effects. Prior to the presentinvention, very little was known about any sedative or hypnotic effectsof ultra low doses of the aforementioned substances.

Some embodiments relate to methods for treating insomnia. The methodscan include, for example, administering to a patient doxepin, apharmaceutically acceptable salt thereof, or a prodrug thereof in anultra low daily dosage. The dosage can be any ultra low dosage, forexample, a dosage ranging from about 0.0001 to about 0.49 milligrams orany other described herein.

Still some embodiments relate to compositions. The compositions caninclude, for example, doxepin, a pharmaceutically acceptable saltthereof, or a prodrug of doxepin in an ultra low dosage. The dosage canbe any ultra low dosage, including any described herein. For example,the dosage can be about 0.0001 milligrams to about 0.49 milligrams.

Also, some embodiments relate to methods of improving or manipulatingthe pharmacokinetics of doxepin, a salt or a prodrug thereof. Themethods can include administering the particular substance (e.g.,doxepin) with or without food, and including information regarding afood effect or instructions to take the doxepin with or without food,for example.

Compounds

Doxepin HCl is a tricyclic compound currently approved and available fortreatment of depression and anxiety. Doxepin belongs to a class ofpsychotherapeutic agents known as dibenzoxepin tricyclic compounds, andis currently approved and prescribed for use as an antidepressant totreat depression and anxiety. Doxepin has a well-established safetyprofile, having been prescribed for over 35 years.

It is contemplated that doxepin for use in the methods described hereincan be obtained from any suitable source or made by any suitable method.As mentioned, doxepin is approved and available in higher doses (75-300milligrams) for the treatment of depression and anxiety. Doxepin HCl isavailable commercially and may be obtained in capsule form from a numberof sources. Doxepin is marketed under the commercial name SINEQUAN® andin generic form, and can be obtained in the United States generally frompharmacies in capsule form in amounts of 10, 25, 50, 75, 100 and 150 mgdosage, and in liquid concentrate form at 10 mg/mL. Doxepin HCl can beobtained from Plantex Ltd. Chemical Industries (Hakadar Street,Industrial Zone, P.O. Box 160, Netanya 42101, Israel), Sifavitor S.p.A.(Via Livelli 1—Frazione, Mairano, Italy), or from Dipharma S.p.A. (20021Baranzate di Bollate, Milano, Italy). Also, doxepin is commerciallyavailable from PharmacyRx (NZ) (2820 1^(st) Avenue, Castlegar, B.C.,Canada) in capsule form in amounts of 10, 25, 50, 75, 100 and 150 mg.Furthermore, Doxepin HCl is available in capsule form in amounts of 10,25, 50, 75, 100 and 150 mg and in a 10 mg/m1 liquid concentrate from CVSOnline Pharmacy Store (CVS.com).

The recommended daily dose for the treatment of depression or anxietyranges from 75 milligrams to 300 milligrams. Also, U.S. Pat. Nos.5,502,047 and 6,211,229, the entire contents of which are incorporatedherein by reference, describe the use of doxepin for the treatmentchronic and non-chronic (e.g., transient/short term) insomnias atdosages below those used to treat depression. Doxepin can be obtainedfrom any suitable source or prepared according to any suitable method.For example, it can be prepared according to the method described inU.S. Pat. No. 3,438,981, which is incorporated herein by reference inits entirety. As another illustration, doxepin can be prepared as taughtin U.S. Pat. No. 3,420,851, which is incorporated herein by reference inits entirety.

Pharmaceutically Acceptable Salts:

As mentioned above, the methods and other embodiments described hereincan utilize any suitable pharmaceutically acceptable salt or prodrug ofdoxepin. Therefore, the substitution or use in combination of salts andprodrugs is specifically contemplated in the embodiments describedherein. The pharmaceutically acceptable salts and prodrugs can be madeby any suitable method. The acids that may be used to preparepharmaceutically acceptable acid addition salts are those that formnon-toxic acid addition salts, i.e., salts containing pharmacologicallyacceptable anions, such as the acetate, benzenesulfonate, benzoate,bicarbonate, bisulfate, bitartrate, borate, bromide, calcium edetate,camsylate, carbonate, chloride, clavulanate, citrate, dihydrochloride,edetate, dislyate, estolate, esylate, ethylsuccinate, fumarate,gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate,hydrabamine, hydrobromide, hydrochloride, iodide, isothionate, lactate,lactobionate, laurate, malate, maleate, mandelate, mesylate,methylsulfate, mucate, napsylate, nitrate, oleate, oxalate, pamoate(embonate), palmitate, pantothenate, phospate/diphosphate,polygalacturonate, salicylate, stearate, subacetate, succinate, tannate,tartrate, teoclate, tosylate, triethiodode, and valerate salts.

Prodrugs:

The term “prodrug” refers to a chemical entity that is rapidlytransformed in vivo to yield an active entity, such as by hydrolysis inblood or inside tissues, for example.

Examples of prodrug groups can be found in, for example, T. Higuchi andV. Stella, in “Pro-drugs as Novel Delivery Systems,” Vol. 14, A.C.S.Symposium Series, American Chemical Society (1975); H. Bundgaard,“Design of Prodrugs,” Elsevier Science, 1985; and “BioreversibleCarriers in Drug Design: Theory and Application,” edited by E. B. Roche,Pergamon Press: New York, 14-21 (1987), each of which is herebyincorporated by reference in its entirety.

Insomnia

As mentioned above, some embodiments relate to the use of ultra lowdoses of doxepin, pharmaceutically acceptable salts, and/or prodrugs inthe treatment of chronic and non-chronic insomnia. Examples ofnon-chronic insomnia include, for example, transient insomnia andshort-term insomnia. Transient insomnia is an insomnia that is presentfor about one to several days, and is less than one week in duration.Short term insomnia is insomnia of about one to three weeks or fourweeks in duration. Chronic insomnia is typically accepted to involveepisodes greater than three (3) or four (4) weeks in duration. It iswell known that the sleep deprivation resulting from such insomniaadversely affects cognition, safety and quality of life.

Furthermore, for chronic (e.g., greater than 3-4 weeks) or non-chronicinsomnias, a patient may suffer from difficulties in sleep onset, sleepmaintenance (interruption of sleep during the night by periods ofwakefulness), sleep duration, sleep efficiency, premature early-morningawakening, or a combination thereof. Also, the insomnia may beattributable to the concurrent use of other medication, for example.

The chronic or non-chronic insomnia can be a primary insomnia or aninsomnia that is secondary or attributable to another condition, forexample a disease such as depression or chronic fatigue syndrome. Insome aspects, the patient can be one that is not suffering from aninsomnia that is a component of a disease. In some aspects, the methodscan specifically exclude a patient with a secondary insomnia, forexample, a patient suffering from insomnia as a component of depressionor chronic fatigue syndrome. Some embodiments relate to methods oftreating individuals suffering from insomnia that is caused by injury orthe use of a medication or other substance. Treating such patients canspecifically be excluded from other methods of treatment.

As previously mentioned, the chronic or non-chronic insomnia can be aprimary insomnia, that is, one that is not attributable to anothermental disorder, a general medical condition, or a substance. In manycases, such conditions may be associated with a chronic insomnia and caninclude, but are not limited to, insomnia attributable to a diagnosableDSM-IV disorder, a disorder such as anxiety or depression, or adisturbance of the physiological sleep-wake system. The non-chronic orshort duration insomnia (e.g., less than 3-4 weeks) can have intrinsicor extrinsic causes. For example, non-chronic sleep disorders caninclude, but are not limited to, environmental sleep disorders asdefined by the International Classification of Sleep Disorders (ICSD)such as inadequate sleep hygiene, altitude insomnia or adjustment sleepdisorder (e.g., bereavement). Also, short-term insomnia may also becaused by disturbances such as shift-work sleep disorder.

In some embodiments, an otherwise healthy individual can be treated forinsomnia. For example, doxepin (or any of the other ultra low dosesubstances) can be used to treat an individual suffering from aninsomnia that is not attributable to a medical, psychiatric, orenvironmental cause. In some embodiments, methods of treating otherwisehealthy individual can be specifically excluded from the methods.

In some embodiments an individual having a secondary insomnia, forexample, insomnia as a component of his/her depression or other illness,can be treated, while in others methods of treatment of such individualscan be specifically excluded. Also, in some embodiments, an individualsuffering from insomnia as part of chronic fatigue syndrome can betreated, while in other embodiments such the treatment of suchindividuals is excluded. Some embodiments relate to methods of treatingindividuals suffering from insomnia that is caused by injury or the useof a medication or other substance. Treating such patients canspecifically be excluded from other methods of treatment.

Also, some embodiments can include the use of low doses of doxepin,prodrugs or salts of the same in combination with other insomnia orsleep medications. For example, the methods can include the use of oneor more of ramelteon, eszopiclone, zolpidem tartrate, zaleplon or thelike. Further, the methods can include the use of one or more of 5-HT2antagonists (such as ketanserin), H3 agonists, orexin antagonists,noradrenergic antagonists, galanin agonists, CRH antagonists, Gaboxadol,other GABA-A direct antagonists, GABA reuptake inhibitors (such astiagabine), growth hormone and growth hormone agonists, estrogen andestrogen agonists, melatonin agonists or the like. Other examples ofmedications and substances that can be used in combination with ultralow doses as described herein can be found in U.S. ProvisionalApplication No. 60/873,056, filed on Dec. 6, 2006, entitled COMBINATIONTHERAPY USING LOW-DOSE DOXEPIN FOR THE IMPROVEMENT OF SLEEP; and U.S.Provisional Application No. 60/910,586, filed on Apr. 6, 2007, entitledCOMBINATION THERAPY USING LOW-DOSE DOXEPIN FOR THE IMPROVEMENT OF SLEEP;each of which applications is incorporated herein by reference in itsentirety.

Food Effect

It also should be mentioned that food can have an effect on thepharmacokinetics of sleep medication. The term “food effect” refers to asomewhat unpredictable phenomenon that can influence the absorption ofdrugs from the gastrointestinal tract following oral administration. Thefood effect can be designated “negative” when absorption is decreased,or “positive” when absorption is increased and manifested as an increasein oral bioavailability (as reflected by total exposure, usually definedas AUC). Alternatively, food effects can refer to changes in maximumconcentration (C_(max)), or the time to reach maximum concentration(T_(max))), independently of overall absorption. As a result, some drugshave to be taken in either fasted or fed conditions to achieve theoptimum effect. For example, patients may be instructed to take a drugwith a meal, before a meal (e.g., one hour before a meal), or after ameal (e.g., two hours after a meal). However, many drugs are unaffectedby food, and thus, can be taken in a fasted or a fed condition.

Accordingly, some embodiments relate to methods of improving thepharmacokinetics of doxepin, as well as the salts and prodrugs of suchsubstances in a patient. In particular, the time to reach maximumconcentration, T_(max), can be minimized by administering the drugwithout food. Also, the time to reach maximum concentration can beincreased by administering the substance with food. In addition, in adifferent embodiment, the total effective amount of drug that thepatient receives can be maximized by administering the substance withfood, while in other embodiments the oral bioavailability can bedecreased by administering the substance without food. Because plasmaconcentrations and half-lives are already known to vary from patient topatient, knowledge of the food effect for a substance can help patientsand physicians to eliminate this additional source of dosinguncertainty, to improve safety and tolerability, and improve therapiesthat utilize doxepin, or salts/prodrugs of the same. For example, asdescribed more fully elsewhere herein, depending on the effect desired,the particular ultra low dose substance, such as an ultra low dose ofdoxepin, can be taken with food; it can be taken after the patient hasgone without food for a period of time; and/or it can be taken someperiod of time prior to consuming food.

In some aspects, information regarding a food effect can be given to apatient or included with the drug. For example, instructions may beprovided to patients receiving doxepin therapy or health careprofessionals involved in treatment of those patients that the drugshould be administered with food, or at least in relatively closeproximity to eating food or eating a meal (for example, within one houror less). By way of example, such instructions could be provided orallyor in written form. Some exemplary written forms include a labelassociated with the drug, on the container for the drug, packaged withthe drug, or separately given to the patient apart from the drug. Theinvention further includes a package of any of the ultra low dosesubstances described herein with such written instructions associatedtherewith.

As mentioned, the ultra low dose substance can be administered withoutfood or in a fasted state. For example, doxepin, prodrug, or salt can beadministered at least about 30 minutes to about 6 hours after consumingfood. More preferably, the substance can be taken at least about 1 hourto about 6 hours after consuming food. In some aspects the substance canbe taken at least about 1, 2, 3, 4, 5 6 or more hours after consumingfood.

Also, the ultra low dose substance can be administered at least about 30minutes to about 6 hours before consuming any food, or more preferably,at least about 1 hour to about 3 hours before consuming food. In someaspects, the ultra low dose substance can be administered about 1, 2, 3or more hours before food is consumed.

It should be understood that the above-mentioned “food effect” methodsand uses can further include the use of doxepin, prodrugs or salts ofthe same in combination with other insomnia or sleep medications. Forexample, the methods can include the use of one or more of ramelteon,eszopiclone, zolpidem tartrate, zaleplon or the like. Further, themethods can include the use of one or more of 5-HT2 antagonists (such asketanserin), H3 agonists, orexin antagonists, noradrenergic antagonists,galanin agonists, CRH antagonists, Gaboxadol, other GABA-A directantagonists, GABA reuptake inhibitors (such as tiagabine), growthhormone and growth hormone agonists, estrogen and estrogen agonists,melatonin agonists or the like. Other examples of medications andsubstances that can be used in combination with ultra low doses asdescribed herein can be found in U.S. Provisional Application No.60/873,056, filed on Dec. 6, 2006, entitled COMBINATION THERAPY USINGLOW-DOSE DOXEPIN FOR THE IMPROVEMENT OF SLEEP; and U.S. ProvisionalApplication No. 60/910,586, filed on Apr. 6, 2007, entitled COMBINATIONTHERAPY USING LOW-DOSE DOXEPIN FOR THE IMPROVEMENT OF SLEEP; each ofwhich applications is incorporated herein by reference in its entirety.

Pharmaceutical Compositions and Administration

As discussed above, doxepin, pharmaceutically acceptable salts, prodrugsand compositions that include any of the same can be used to treatinsomnia in a mammal, including a human. Such compositions can be usedalone, in combination with other substances or the compositions canfurther include the other substances. For example, the substances caninclude other insomnia or sleep medications, or other medications thattreat a primary illness. For example, doxepin, prodrugs or salts of thesame can be used or administered with ramelteon, eszopiclone, zolpidemtartrate, zaleplon or the like. Further, doxepin, prodrugs or salts ofthe same can be administered with one or more of 5-HT2 antagonists (suchas ketanserin), H3 agonists, orexin antagonists, noradrenergicantagonists, galanin agonists, CRH antagonists, Gaboxadol, other GABA-Adirect antagonists, GABA reuptake inhibitors (such as tiagabine), growthhormone and growth hormone agonists, estrogen and estrogen agonists,melatonin agonists or the like. Other examples of medications andsubstances that can be used in combination with ultra low doses asdescribed herein can be found in U.S. Provisional Application No.60/873,056, filed on Dec. 6, 2006, entitled COMBINATION THERAPY USINGLOW-DOSE DOXEPIN FOR THE IMPROVEMENT OF SLEEP; and U.S. ProvisionalApplication No. 60/910,586, filed on Apr. 6, 2007, entitled COMBINATIONTHERAPY USING LOW-DOSE DOXEPIN FOR THE IMPROVEMENT OF SLEEP; each ofwhich applications is incorporated herein by reference in its entirety.Methods of use can include the step of administering a therapeuticallyeffective amount of the composition or a compound(s) to a mammal in needthereof.

Actual dosage levels of the compound(s) in the pharmaceuticalcompositions may be varied so as to administer an amount of the compoundthat is effective to achieve the desired therapeutic response for aparticular patient. Examples of dosages that can be used are describedmore fully elsewhere herein.

Suitable routes of administration include oral, buccal, sublingual,transdermal, rectal, topical, transmucosal, or intestinaladministration; parenteral delivery, including intramuscular,subcutaneous, intravenous, intramedullary injections, as well asintrathecal, direct intraventricular, intraperitoneal, intranasal, orintraocular injections.

For oral administration, the compounds can be formulated readily bycombining the active compound(s) with pharmaceutically acceptablecarriers well known in the art. Such carriers enable the compounds ofthe invention to be formulated as tablets, pills, dragees, capsules,liquids, gels, syrups, slurries, suspensions and the like, for oralingestion by a patient to be treated. Administration though oralpathways can be accomplished, for example, using a capsule, a tablet, agranule, a spray, a syrup, a liquid, powder, granules, pastes (e.g., forapplication to the tongue). Oral administration can be accomplishedusing fast-melt formulations, for example. Pharmaceutical preparationsfor oral use can be obtained by mixing one or more solid excipient withpharmaceutical compound as described herein, optionally grinding theresulting mixture, and processing the mixture of granules, after addingsuitable auxiliaries, if desired, to obtain tablets or dragee cores.Suitable excipients are, in particular, fillers such as sugars,including lactose, sucrose, mannitol, or sorbitol; cellulosepreparations such as, for example, maize starch, wheat starch, ricestarch, potato starch, gelatin, gum tragacanth, methyl cellulose,hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose, and/orpolyvinylpyrrolidone (PVP). If desired, disintegrating agents may beadded, such as the cross-linked polyvinyl pyrrolidone, agar, or alginicacid or a salt thereof such as sodium alginate.

Pharmaceutical preparations which can be used orally, includingsublingually, include for example, liquid solutions, powders, andsuspensions in bulk or unit dosage forms. Also, the oral formulationscan include, for example, pills, tablets, granules, sprays, syrups,pastes, powders, boluses, pre-measured ampules or syringes, push-fitcapsules made of gelatin, as well as soft, sealed capsules made ofgelatin and a plasticizer, such as glycerol or sorbitol. The push-fitcapsules can contain the active ingredients in admixture with fillersuch as lactose, binders such as starches, and/or lubricants such astalc or magnesium stearate and, optionally, stabilizers. In softcapsules, the active compounds may be dissolved or suspended in suitableliquids, such as fatty oils, liquid paraffin, or liquid polyethyleneglycols. In addition, stabilizers may be added. All formulations fororal administration should be in dosages suitable for suchadministration.

For buccal administration, the compositions may take any suitable form,for example, tablets or lozenges.

For topical administration, the compound(s) may be formulated foradministration to the epidermis as ointments, gels, creams, pastes,salves, gels, creams or lotions, or as a transdermal patch. Ointmentsand creams may, for example, be formulated with an aqueous or oily basewith the addition of suitable thickening and/or gelling agents. Lotionsmay be formulated with an aqueous or oily base and will in general alsocontaining one or more emulsifying agents, stabilizing agents,dispersing agents, suspending agents, thickening agents, or coloringagents.

For injection, the compound(s) or compositions may be formulated inaqueous solutions, preferably in physiologically compatible buffers suchas Hanks's solution, Ringer's solution, or physiological saline buffer.For transmucosal administration, penetrants appropriate to the barrierto be permeated are used in the formulation. Such penetrants aregenerally known in the art.

For administration by inhalation, the compound(s) for use according tothe present invention are conveniently delivered in the form of anaerosol spray presentation from pressurized packs or a nebulizer, withthe use of a suitable propellant, e.g., dichlorodifluoromethane,trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide, orother suitable gas. In the case of a pressurized aerosol the dosage unitmay be determined by providing a valve to deliver a metered amount.Capsules and cartridges of, e.g., gelatin for use in an inhaler orinsufflator may be formulated containing a powder mix of the compoundand a suitable powder base such as lactose or starch.

The compound(s) may be formulated for parenteral administration byinjection, e.g., by bolus injection or continuous infusion. Formulationsfor injection may be presented in unit dosage form, e.g., in ampoules orin multi-dose containers, with an added preservative. The compositionsmay take such forms as suspensions, solutions or emulsions in oily oraqueous vehicles, and may contain formulatory agents such as suspending,stabilizing and/or dispersing agents.

Pharmaceutical formulations for parenteral administration includeaqueous solutions of the active compound(s) in water-soluble form.Additionally, suspensions of the active compounds may be prepared asappropriate oily injection suspensions. Suitable lipophilic solvents orvehicles include fatty oils such as sesame oil, or synthetic fatty acidesters, such as ethyl oleate or triglycerides, or liposomes. Aqueousinjection suspensions may contain substances which increase theviscosity of the suspension, such as sodium carboxymethyl cellulose,sorbitol, or dextran. Optionally, the suspension may also containsuitable stabilizers or agents which increase the solubility of thecompounds to allow for the preparation of highly concentrated solutions.

In addition, any of the compound(s) and compositions described hereincan also be formulated as a depot preparation. Such long actingformulations may be administered by implantation (for examplesubcutaneously or intramuscularly) or by intramuscular injection. Thus,for example, the compound(s) may be formulated with suitable polymericor hydrophobic materials (for example as an emulsion in an acceptableoil) or ion exchange resins, or as sparingly soluble derivatives, forexample, as a sparingly soluble salt. Furthermore, any of thecompound(s) and compositions described herein also can be formulated asa fast-melt preparation. The compound(s) and compositions can also beformulated and administered as a drip, a suppository, a salve, anointment, an absorbable material such a transdermal patch, or the like.

One can also administer the compound(s) of the invention in sustainedrelease forms or from sustained release drug delivery systems. Adescription of representative sustained release materials can be foundin the incorporated materials in Remington: The Science and Practice ofPharmacy (20^(th) ed, Lippincott Williams & Wilkens Publishers (2003)),which is incorporated herein by reference in its entirety.

A variety of techniques for formulation and administration can be foundin Remington: The Science and Practice of Pharmacy (20^(th) ed,Lippincott Williams & Wilkens Publishers (2003)), which is incorporatedherein by reference in its entirety.

Doxepin, pharmaceutically acceptable salts, and/or prodrugs can beincluded as part of a composition. The compounds and compositions caninclude any suitable form of the compound for pharmaceutical delivery,as discussed in further detail herein. For example, in certainembodiments, the compounds or compositions comprising the same mayinclude a pharmaceutically acceptable salt of the compound.

The compositions and formulations disclosed herein also can include oneor more pharmaceutically acceptable carrier materials or excipients.Such compositions can be prepared for storage and for subsequentadministration. Acceptable carriers or diluents for therapeutic use arewell known in the pharmaceutical art, and are described, for example, inthe incorporated material of Remington: The Science and Practice ofPharmacy (20^(th) ed, Lippincott Williams & Wilkens Publishers (2003)),which is incorporated herein by reference in its entirety. The term“carrier” material or “excipient” herein can mean any substance, notitself a therapeutic agent, used as a carrier and/or diluent and/oradjuvant, or vehicle for delivery of a therapeutic agent to a subject oradded to a pharmaceutical composition to improve its handling or storageproperties or to permit or facilitate formation of a dose unit of thecomposition into a discrete article such as a capsule or tablet suitablefor oral administration. Excipients can include, by way of illustrationand not limitation, diluents, disintegrants, binding agents, adhesives,wetting agents, polymers, lubricants, glidants, substances added to maskor counteract a disagreeable taste or odor, flavors, dyes, fragrances,and substances added to improve appearance of the composition.Acceptable excipients include lactose, sucrose, starch powder, maizestarch or derivatives thereof, cellulose esters of alkanoic acids,cellulose alkyl esters, talc, stearic acid, magnesium stearate,magnesium oxide, sodium and calcium salts of phosphoric and sulfuricacids, gelatin, acacia gum, sodium alginate, polyvinyl-pyrrolidone,and/or polyvinyl alcohol, saline, dextrose, mannitol, lactose, lecithin,albumin, sodium glutamate, cysteine hydrochloride, and the like.Examples of suitable excipients for soft gelatin capsules includevegetable oils, waxes, fats, semisolid and liquid polyols. Suitableexcipients for the preparation of solutions and syrups include, withoutlimitation, water, polyols, sucrose, invert sugar and glucose. Suitableexcipients for injectable solutions include, without limitation, water,alcohols, polyols, glycerol, and vegetable oils. The pharmaceuticalcompositions can additionally include preservatives, solubilizers,stabilizers, wetting agents, emulsifiers, sweeteners, colorants,flavorings, buffers, coating agents, or antioxidants. Sterilecompositions for injection can be formulated according to conventionalpharmaceutical practice as described in the incorporated material inRemington: The Science and Practice of Pharmacy (20^(th) ed, LippincottWilliams & Wilkens Publishers (2003)). For example, dissolution orsuspension of the active compound in a vehicle such as water ornaturally occurring vegetable oil like sesame, peanut, or cottonseed oilor a synthetic fatty vehicle like ethyl oleate or the like may bedesired. Buffers, preservatives, antioxidants and the like can beincorporated according to accepted pharmaceutical practice. The compoundcan also be made in microencapsulated form. In addition, if desired, theinjectable pharmaceutical compositions may contain minor amounts ofnontoxic auxiliary substances, such as wetting agents, pH bufferingagents, and the like. If desired, absorption enhancing preparations (forexample, liposomes), can be utilized.

The compositions and formulations can include any other agents thatprovide improved transfer, delivery, tolerance, and the like. Thesecompositions and formulations can include, for example, powders, pastes,ointments, jellies, waxes, oils, lipids, lipid (cationic or anionic)containing vesicles (such as Lipofectin™), DNA conjugates, anhydrousabsorption pastes, oil-in-water and water-in-oil emulsions, emulsionscarbowax (polyethylene glycols of various molecular weights), semi-solidgels, and semi-solid mixtures containing carbowax. Any of the foregoingmixtures may be appropriate in treatments and therapies in accordancewith the present invention, provided that the active ingredient in theformulation is not inactivated by the formulation and the formulation isphysiologically compatible and tolerable with the route ofadministration. See also Baldrick P. “Pharmaceutical excipientdevelopment: the need for preclinical guidance.” Regul. Toxicol.Pharmacol. 32(2):210-8 (2000), Charman WN “Lipids, lipophilic drugs, andoral drug delivery-some emerging concepts.” J Pharm Sci 0.89(8):967-78(2000), Powell et al. “Compendium of excipients for parenteralformulations” PDA J Pharm Sci Technol. 52:238-311 (1998) and thecitations therein for additional information related to formulations,excipients and carriers well known to pharmaceutical chemists.

The selected dosage level can depend upon, for example, the route ofadministration, the severity of the condition being treated, and thecondition and prior medical history of the patient being treated.However, it is within the skill of the art to start doses of thecompound at levels lower than required to achieve the desiredtherapeutic effect and to gradually increase the dosage until thedesired effect is achieved. It will be understood, however, that thespecific dose level for any particular patient can depend upon a varietyof factors including the genetic makeup, body weight, general health,diet, time and route of administration, combination with other drugs andthe particular condition being treated, and its severity. For thetreatment of insomnia, preferably one dose is administered prior tobedtime.

Dosages

Any suitable dosage of doxepin, a pharmaceutical salt, or prodrug can beused to treat the sleep disorder such as insomnia. In some aspects,daily dosages may vary from about 0.0001 to about 0.49 milligrams, fromabout 0.001 to about 0.1 milligrams, or from about 0.01 to about 0.099milligrams. Daily dosages of about 0.2, 0.3, or 0.4 milligrams can beused, for example. Preferably, daily dosages of about 0.01, 0.02, 0.03,0.04, 0.05, 0.06, 0.07, 0.08, 0.09 or 0.1 milligrams can be utilized.Still in some aspects, a dosage of about 0.001, 0.005, or about 0.008milligrams may be used. In other aspects, a daily dosage of less than0.5, less than 0.1 or less than about 0.099 milligrams can be used.However, as it is recognized that each individual may react differentlyto a given dose of the medication used, the dosages recited should beaccorded flexibility. Further, any suitable unit dosage form can beformulated to contain doxepin, a prodrug or a pharmaceuticallyacceptable salt in the above-recited amounts (e.g., 0.0001-0.49 mg).These low doses have reduced side effects, are surprisingly effective,and have a relatively rapid onset.

Some examples, without limitation of dosages of medications andcompounds that can be combined with the ultra low dose compoundsdescribed herein can be found in U.S. Provisional Application No.60/873,056, filed on Dec. 6, 2006, entitled COMBINATION THERAPY USINGLOW-DOSE DOXEPIN FOR THE IMPROVEMENT OF SLEEP; and U.S. ProvisionalApplication No. 60/910,586, filed on Apr. 6, 2007, entitled COMBINATIONTHERAPY USING LOW-DOSE DOXEPIN FOR THE IMPROVEMENT OF SLEEP; each ofwhich applications is incorporated herein by reference in its entirety.

EXAMPLES Example 1 Synthesis of Doxepin(11-(3-dimethylaminopropylidene)-6,11-dihydrodibenzo-[b,e]-oxepine)

Part (a) A Grignard compound was prepared in the conventional mannerfrom 4.8 g (0.2 gram-atom) magnesium in 100 ml ether and 30 g (34 ml)(3-chloropropyl)-tertbutyl-ether and 16.40 grams (0.078 mol)6,11-dihydrodibenzo-[b,e]-oxepine-11-one dissolved in 100 ml ether wereadded in dropwise fashion so that the contents of the flask boiledlightly. The mixture was heated for 1 hour with agitation in a refluxcondenser to complete the reaction and then it was decomposed withammonium chloride solution. The product which was obtained byseparating, drying and eliminating the solvent produced, when the etherresidue (24.0 g) was extracted with ligroin, amounted to 20.3 g (80.0%of theory) of11-(3-tertbutoxypropyl)-11-hydroxy-6,11-dihydrodibenzo-[b,e]-oxepine,having a melting point of 124-126° C. The (3-chloropropyl)-tertbutylether was thereafter obtained in the following manner: 19 g (0.2 mol)1-chloropropanol-(3), 50 ml liquid isobutylene and 0.5 ml concentratedsulfuric acid were permitted to stand for 24 hours in an autoclave, thenpoured into excess sodium bicarbonate solution and extracted with ether.The ether solution was dried with calcium chloride and distilled. 23.6grams of (3-chloropropyl)-tertbutylether having a boiling point of150-156° C. (78% of theory) were recovered.

Part (b) 30.8 grams of the11-(3-tertbutoxypropyl)-11-hydroxy-6,11-dihydrodibenzo-[b,e]-oxepineobtained according to (a) above and 150 ml absolute alcoholichydrochloric acid were heated for 1 hour at ebullition. After removingthe solvent by evaporation, the residue was crystallized with ligroin,21.0 grams (88.5% of theory) of11-(3-hydroxypropylidene)-6,11-dihydrodibenzo-[b,e]-oxepine having amelting point of 108-111° C. were obtained. After recrystallization fromacetic acid ester, the compound melted at 112-114° C.

Part (c) 5.0 ml thionyl chloride dissolved in 5 ml benzene were addeddropwise at room temperature to 12.6 g (0.05 mol) of the11-(3-hydroxypropylidene)-6,11-dihydrodibenzo-[b,e]-oxepine obtained inpart (b) above. After 1 hour of standing, the contents of the flask wereheated at ebullition for 2 hours. The volatile components werethereafter removed and the remainder distilled using high vacuum. Theyield amounted to 10.6 g (78.5% of theory) of11-(3-chloropropylidene)-6,11-dihydrodibenzo-[b,e]-oxepine having aB.P.0.1 169-172° C., a melting point of 106-111° C. Afterrecrystallization from 20 ml of acetic acid ester, 9.1 g (67.5% oftheory) of pure product having a melting point of 113-115° C. wereobtained. The crude product can however be used quite easily for furtherprocessing.

Part (d) 5.4 g (0.02 mol) of the11-(3-chloropropylidene)-6,11-dihydrodibenzo-[b,e]-oxepine, preparedaccording to (c) above, in 20 ml tetrahydrofuran and 5.5 g (0.12 mol)dimethylamine in 20 ml ethanol were heated together for 3 hours using aglass autoclave and a temperature of 95-100° C. (boiling water bath).Water and 6 N hydrochloric acid were added to the contents of theautoclave and the mixture was extracted with ether. The separated,aqueous-acid components were then made alkaline with dilute caustic sodasolution, and the oil thereby separated was taken up in ether. The etherresidue, after distillation in a high vacuum, produced 4.1 g (73.5% oftheory) of11-(3-dimethylamino-propylidene)-6,11-dihydrodibenzo-[b,e]-oxepine,having a B.P.0.1 147-150° C. The melting point of the hydrochloride was182-184° C. (recrystallized from isopropanol).

Example 2

A patient suffers from transient or short term insomnia. The patient isotherwise healthy with normal affect with no depression, anxiety orsubstance overuse. The patient is prescribed doxepin in a daily dosageof 0.4 milligrams, prior to bedtime. Administration of doxepin relievesthe insomnia.

Example 3

A patient suffers from transient or short term insomnia. The patient isotherwise healthy with normal affect with no depression, anxiety orsubstance overuse. The patient is prescribed doxepin in a daily dosageof 0.08 milligrams, prior to bedtime. Administration of doxepin relievesthe insomnia.

Example 4

A patient suffers from transient or short term insomnia. The patient isotherwise healthy with normal affect with no depression, anxiety orsubstance overuse. The patient is prescribed doxepin in a daily dosageof 0.009 milligrams, prior to bedtime. Administration of doxepinrelieves the insomnia.

Example 5

A patient suffers from transient or short term insomnia. The patient isotherwise healthy with normal affect with no depression, anxiety orsubstance overuse. The patient is prescribed doxepin in a daily dosageof 0.0005 milligrams prior to bedtime. Administration of doxepinrelieves the insomnia.

Example 6

A patient suffers from transient or short term insomnia. The patientalso suffers from depression. The patient is prescribed doxepin in adaily dosage of 0.3 milligrams, prior to bedtime. Administration ofdoxepin relieves the insomnia.

Example 7

A patient suffers from transient or short term insomnia. The patientalso suffers from depression. The patient is prescribed doxepin in adaily dosage of 0.1 milligrams, prior to bedtime. Administration ofdoxepin relieves the insomnia.

Example 8

A patient suffers from transient or short term insomnia. The patientalso suffers from depression. The patient is prescribed doxepin in adaily dosage of 0.006 milligrams, prior to bedtime. Administration ofdoxepin relieves the insomnia.

Example 9

A patient suffers from transient or short term insomnia. The patient isotherwise healthy with normal affect with no depression, anxiety orsubstance overuse. The patient is prescribed doxepin in a daily dosageof 0.008 milligrams, prior to bedtime. Administration of doxepinrelieves the insomnia.

Example 10

A patient suffers from transient or short term insomnia. The patientalso suffers from depression. The patient is prescribed doxepin in adaily dosage of 0.001 milligrams, prior to bedtime. Administration ofdoxepin relieves the insomnia.

Example 11

A patient suffers from transient or short term insomnia. The patientalso suffers from depression. The patient is prescribed doxepin in adaily dosage of 0.0003 milligrams prior to bedtime. Administration ofdoxepin relieves the insomnia.

Example 12

A patient suffers from chronic insomnia. The patient is otherwisehealthy with normal affect with no depression, anxiety or substanceoveruse. The patient is prescribed doxepin in a daily dosage of 0.4milligrams prior to bedtime. Administration of doxepin relieves theinsomnia.

Example 13

A patient suffers from chronic insomnia. The patient is otherwisehealthy with normal affect with no depression, anxiety or substanceoveruse. The patient is prescribed doxepin in a daily dosage of 0.2milligrams prior to bedtime. Administration of the doxepin relieves theinsomnia.

Example 14

A patient suffers from chronic insomnia. The patient is otherwisehealthy with normal affect with no depression, anxiety or substanceoveruse. The patient is prescribed doxepin in a daily dosage of 0.02milligrams prior to bedtime. Administration of doxepin relieves theinsomnia.

Example 15

A patient suffers from chronic insomnia. The patient is otherwisehealthy with normal affect with no depression, anxiety or substanceoveruse. The patient is prescribed doxepin in a daily dosage of 0.007milligrams prior to bedtime. Administration of doxepin relieves theinsomnia.

Example 16

A patient suffers from chronic insomnia. The patient is otherwisehealthy with normal affect with no depression, anxiety or substanceoveruse. The patient is prescribed doxepin in a daily dosage of 0.009milligrams prior to bedtime. Administration of doxepin relieves theinsomnia.

Example 17

A patient suffers from chronic insomnia. The patient is otherwisehealthy with normal affect with no depression, anxiety or substanceoveruse. The patient is prescribed doxepin in a daily dosage of 0.0002milligrams prior to bedtime. Administration of doxepin relieves theinsomnia.

Example 18

A patient suffers from chronic insomnia. The patient is otherwisehealthy with normal affect with no depression, anxiety or substanceoveruse. The patient is prescribed doxepin in a daily dosage of 0.0002milligrams prior to bedtime. Administration of doxepin relieves theinsomnia.

Example 19

A patient suffers from chronic insomnia. The patient also suffers fromdepression. The patient is prescribed doxepin in a daily dosage of 0.5milligram prior to bedtime. Administration of doxepin relieves theinsomnia.

Example 20

A patient suffers from chronic insomnia. The patient also suffers fromdepression. The patient is prescribed doxepin in a daily dosage of 0.03milligrams prior to bedtime. Administration of doxepin relieves theinsomnia.

Example 21

A patient suffers from chronic insomnia. The patient also suffers fromdepression. The patient is prescribed doxepin in a daily dosage of 0.05milligrams prior to bedtime. Administration of doxepin relieves theinsomnia.

Example 22

A patient suffers from chronic insomnia. The patient also suffers fromdepression. The patient is prescribed doxepin in a daily dosage of 0.004milligrams prior to bedtime. Administration of doxepin relieves theinsomnia.

Example 23

A patient suffers from chronic insomnia. The patient also suffers fromdepression. The patient is prescribed doxepin in a daily dosage of0.0001 milligrams prior to bedtime. Administration of doxepin relievesthe insomnia.

Example 24

A patient suffers from chronic insomnia. The patient also suffers fromdepression. The patient is prescribed doxepin in a daily dosage of0.0009 milligrams prior to bedtime. Administration of the doxepinrelieves the insomnia.

Example 25

A patient suffers from a sleep disorder. The patient is prescribeddoxepin in a daily dosage of 0.1 milligram prior to bedtime.Administration of the doxepin relieves the insomnia.

Example 26

A patient suffers from a sleep disorder. The patient is prescribed apharmaceutically acceptable salt of doxepin in a daily dosage of 0.3milligrams prior to bedtime. Administration of the pharmaceuticallyacceptable salt of doxepin relieves the insomnia.

Example 27

A patient suffers from a sleep disorder. The patient is prescribed apharmaceutically acceptable salt of doxepin in a daily dosage of 0.009milligrams prior to bedtime. Administration of the pharmaceuticallyacceptable salt of doxepin relieves the insomnia.

Example 28

A patient suffers from a sleep disorder. The patient is prescribed apharmaceutically acceptable salt of doxepin in a daily dosage of 0.006milligrams prior to bedtime. Administration of the pharmaceuticallyacceptable salt relieves the insomnia.

Example 29

A patient suffers from a sleep disorder. The patient is prescribed apharmaceutically acceptable salt of doxepin in a daily dosage of 0.0007milligrams prior to bedtime. Administration of the pharmaceuticallyacceptable salt of doxepin relieves the insomnia.

Example 30

A patient suffers from a sleep disorder. The patient is prescribed aprodrug of doxepin in a daily dosage of 0.1 milligrams prior to bedtime.Administration of the prodrug relieves the insomnia.

Example 31

A patient suffers from a sleep disorder. The patient is prescribed aprodrug of doxepin in a daily dosage of 0.0006 milligrams prior tobedtime. Administration of the prodrug relieves the insomnia.

Example 32

A patient suffers from a sleep disorder. The patient is prescribed aprodrug of doxepin in a daily dosage of 0.05 milligrams prior tobedtime. Administration of the prodrug relieves the insomnia.

Example 33

A patient suffers from a sleep disorder. The patient is prescribed aprodrug of doxepin in a daily dosage of 0.004 milligrams prior tobedtime. Administration of the prodrug relieves the insomnia.

Example 34

A patient suffers from a sleep disorder. The patient is prescribed aprodrug of doxepin in a daily dosage of 0.0009 milligrams prior tobedtime. Administration of the prodrug relieves the insomnia.

Example 35 Assessment of the Effect of Food on the Pharmacokinetics ofDoxepin, a Pharmaceutically Acceptable Salt of Doxepin, or a Prodrug orDoxepin

A study assesses the effect of food on the pharmacokinetics (PK) ofdoxepin, a pharmaceutically acceptable salt of doxepin or a prodrug ofdoxepin in healthy subjects. Subjects receive ultra low doses of thesubject compounds in the morning under either fed or fasted conditions.All subjects are dosed under both fed and fasted conditions during thestudy.

Subjects being dosed under fasted conditions are required to fastovernight for at least 10 hours prior to study drug administration andfor 4 hours after study drug administration. Fluids are restricted from1 hour predose to 1 hour postdose, except for water taken at the time ofdosing. Subjects being dosed under fed conditions are dosedapproximately 5 minutes after eating a high-fat, high-caloriestandardized breakfast (to be ingested within 25 minutes). Subjects arerequired to ingest the entire contents of the breakfast. All subjectsare required to remain in bed for approximately 4 hours after dosing.

Contents of the high-fat, high-calorie standardized breakfast are:

Two eggs fried in butter;

Two slices of bacon;

240 mL (8 fl. oz) whole milk;

57 g (2 oz) of hash browned potatoes; and

Two slices of toasted white bread with butter.

The total amount of protein, fat, and carbohydrate that make up thismeal is approximately 33, 55, and 58 g, respectively. The total caloriecontent is approximately 850 kcal.

The PK profiles are evaluated. Blood samples are collected at predose (0hour) and at various postdose time points (e.g., 0.08, 0.17, 0.25, 0.5,0.75, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36, 48, 60, 72, and 96 hourspostdose). The samples are analyzed for concentrations of the testcompound in plasma. Plasma concentrations are measured using validatedhigh performance liquid chromatography coupled to tandem massspectrometry. The following PK parameters are estimated bynoncompartmental methods using actual elapsed time from dosing:

C_(max) (ng/mL) Maximum observed plasma concentration, obtained directlyfrom the observed concentration versus time data. T_(max) (h) Time tomaximum plasma concentration, obtained directly from the observedconcentration versus time data. AUC_(0-∞) (ng · h/mL) Area under thecurve from time zero extrapolated to infinity, calculated by linearup/log down trapezoidal summation and extrapolated to infinity byaddition of the last quantifiable concentration divided by theelimination rate constant (AUC_(0-Tlast) + C_(last)/λ_(z)). If theextrapolated area (C_(last)/λ_(z)) was greater than 30% of AUC_(0-∞),then AUC_(0-∞) was set to missing. AUC_(0-Tlast) (ng · h/mL) Area underthe curve from time zero to time of last measurable concentration,calculated by linear up/log down trapezoidal summation. AUC₀₋₂₄ (ng ·h/mL) Area under the curve from time zero until 24 hours, calculated bylinear up/log down trapezoidal summation. If the 24 h sample was missingor below the lower limit of quantification, AUC_(0-Tlast) was to bereported as AUC₀₋₂₄. AUC₀₋₄₈ (ng · h/mL) Area under the curve from timezero until 48 hours, calculated by linear up/log down trapezoidalsummation. If the 48 h sample was missing or below the lower limit ofquantification, AUC_(0-Tlast) was to be reported as AUC₀₋₄₈. AUC₀₋₇₂ (ng· h/mL) Area under the curve from time zero until 72 hours, calculatedby linear up/log down trapezoidal summation. If the 72 h sample wasmissing or below the lower limit of quantification, AUC_(0-Tlast) was tobe reported as AUC₀₋₇₂. AUC₀₋₉₆ (ng · h/mL) Area under the curve fromtime zero until 96 hours, calculated by linear up/log down trapezoidalsummation. If the 96 h sample was missing or below the lower limit ofquantification, AUC_(0-Tlast) was to be reported as AUC₀₋₉₆. λ_(z) (l/h)Elimination rate constant associated with the terminal (log- linear)portion of the curve. This was estimated via linear regression of timeversus log concentration. Visual assessment was used to identify theterminal linear phase of the concentration-time profile. A minimum ofthree data points were used for determination. t_(1/2) (h) Apparentterminal half-life, determined as ln2/λ_(z). CL/F (L/h) Apparent oralclearance, calculated as dose divided by AUC_(0-∞). Vd/F (L) Apparentvolume of distribution, calculated as (CL/F)/λ_(z).

Many modifications and variations of the embodiments described hereinmay be made without departing from the scope, as is apparent to thoseskilled in the art. The specific embodiments described herein areoffered by way of example only.

1. A method for treating insomnia comprising administering to a patientdoxepin, a pharmaceutically acceptable salt thereof, or a prodrugthereof in a daily dosage ranging from about 0.0001 to about 0.49milligrams.
 2. The method of claim 1, wherein the pharmaceuticallyacceptable salt of doxepin is the hydrochloride salt thereof.
 3. Themethod of claim 1, wherein the prodrug of doxepin is a prodrug ester. 4.The method of claim 1, wherein the daily dosage is about 0.0001 to about0.1 milligrams.
 5. The method of claim 1, wherein the daily dosageranges from about 0.001 to about 0.1 milligrams.
 6. The method of claim1, wherein the daily dosage is about 0.01 to about 0.099 milligrams. 7.The method of claim 1, wherein the insomnia is a chronic insomnia or anon-chronic insomnia.
 8. The method of claim 7, wherein the non-chronicinsomnia is a transient or a short term insomnia.
 9. The method of claim1, wherein the insomnia is selected from the group consisting of onsetinsomnia and maintenance insomnia.
 10. The method of any of claims 1-9,wherein the patient is not suffering from depression.
 11. The method ofany of claims 1-9, wherein the patient is suffering from depression. 12.The method of claim 1, further comprising administering at least one oframelteon, eszopiclone, zolpidem tartrate, or zaleplon.
 13. The methodof claim 1, further comprising administering at least one additionalsleep medication.
 14. The method of claim 13, wherein the at least oneadditional sleep medication is selected from a 5-HT2 antagonist,ketanserin, a H3 agonist, an orexin antagonist, a noradrenergicantagonist, a galanin agonist, a CRH antagonist, Gaboxadol, other GABA-Adirect antagonists, a GABA reuptake inhibitor, tiagabine, a growthhormone, a growth hormone agonist, estrogen, an estrogen agonist, or amelatonin agonist.
 15. A composition comprising doxepin, apharmaceutically acceptable salt thereof, or a prodrug of doxepin in adosage of about 0.0001 milligrams to about 0.49 milligrams.
 16. Thecomposition of claim 15, further comprising a pharmaceuticallyacceptable carrier.
 17. The composition of claim 15, wherein thepharmaceutically acceptable salt of doxepin is the hydrochloride saltthereof.
 18. The composition of claim 15, wherein the prodrug is anester.
 19. The composition of claim 15, comprising a dosage of about0.001 to about 0.1 milligrams of doxepin, a pharmaceutically acceptablesalt of doxepin or a prodrug doxepin.
 20. The composition of claim 15,comprising a dosage of about 0.01 to about 0.099 milligrams of doxepin,a pharmaceutically acceptable salt of doxepin or a prodrug of doxepin.21. The composition of claim 15, wherein the composition is in a formsuitable for oral or nasal administration.
 22. The composition of any ofclaim 15, 16, 17, 18, 19, 20, or 21, further comprising at least one oframelteon, eszopiclone, zolpidem tartrate, or zaleplon.
 23. Thecomposition of any of claim 15, 16, 17, 18, 19, 20, or 21, furthercomprising at least one additional sleep medication.
 24. The compositionof claim 25, wherein the at least one additional sleep medication isselected from a 5-HT2 antagonist, ketanserin, a H3 agonist, an orexinantagonist, a noradrenergic antagonist, a galanin agonist, a CRHantagonist, Gaboxadol, other GABA-A direct antagonists, a GABA reuptakeinhibitor, tiagabine, a growth hormone, a growth hormone agonist,estrogen, an estrogen agonist, or a melatonin agonist.
 25. A method ofshortening the time required to achieve a maximum plasma concentrationof doxepin in a patient receiving doxepin therapy comprisingadministering to the patient about 0.0001 milligrams to about 0.49milligrams of doxepin in a pharmaceutical composition without food. 26.A method of shortening the time required to achieve sleep onsetcomprising administering to the patient about 0.0001 milligrams to about0.49 milligrams of doxepin in a pharmaceutical composition without food.27. A method of treating a sleep disorder comprising providing a patientwith about 0.0001 milligrams to about 0.49 milligrams of doxepin andproviding the patient with instructions to take the doxepin withoutfood.
 28. A method of increasing the oral bioavailability of doxepin,comprising administering with food to a patient a pharmaceutical oraldosage form of doxepin in an amount of about 0.0001 milligrams to about0.49 milligrams.
 29. A method of increasing the oral bioavailability ofdoxepin to a patient receiving doxepin therapy, comprising administeringto the patient with food a pharmaceutical oral dosage form of doxepincomprising about 0.0001 milligrams to about 0.49 milligrams of doxepin,wherein the administration results in an AUC_(0-∞), that is greater thanthat achieved by the administration of the same amount of doxepinwithout food.
 30. A method of treating depression or anxiety, comprisingadministering about 0.0001 milligrams to about 0.49 milligrams ofdoxepin with food.
 31. A method of treating depression or anxiety,comprising providing a patient with doxepin in an amount of about 0.0001milligrams to about 0.49 milligrams and providing the patient withinstructions to take the doxepin with food.
 32. A method of treatingdepression or anxiety comprising providing a patient with doxepin in anamount of about 0.0001 milligrams to about 0.49 milligrams and providingthe patient with information regarding a doxepin food effect.
 33. Amethod of decreasing the oral bioavailability of doxepin, comprisingadministering to a patient a pharmaceutical oral dosage form of doxepincomprising doxepin in an amount of about 0.0001 milligrams to about 0.49milligrams without food.
 34. A method of decreasing the oralbioavailability of doxepin to a patient receiving doxepin therapy,comprising administering to the patient without food a pharmaceuticaloral dosage form of doxepin comprising doxepin in an amount of about0.0001 milligrams to about 0.49 milligrams, wherein the administrationresults in an AUC_(0-∞) that is less than that achieved by theadministration of the same amount of doxepin with food.
 35. A method ofalleviating a doxepin food effect comprising administering about 0.0001milligrams to about 0.49 milligrams of doxepin to a patient in needthereof, wherein the patient is in a non-fasted state.
 36. A method ofalleviating a doxepin food effect comprising administering about 0.0001milligrams to about 0.49 milligrams of doxepin to a patient in needthereof, wherein the patient is in a fasted state.
 37. A method ofminimizing side effects associated with a doxepin therapy, comprisingadministering about 0.0001 milligrams to about 0.49 milligrams ofdoxepin to a patient with food.
 38. A method for improving theconsistency of pharmacokinetics associated with doxepin therapy, inwhich a patient receives a multiple doxepin dosages over multiple days,comprising administering about 0.0001 milligrams to about 0.49milligrams of doxepin to the patient in a fixed temporal relationship tofood intake by the patient.
 39. A product comprising doxepin in anamount of about 0.0001 milligrams to about 0.49 milligrams and writteninstructions associated therewith to take the doxepin without food. 40.A product comprising doxepin in an amount of about 0.0001 milligrams toabout 0.49 milligrams and written instructions associated therewith totake the doxepin with food.
 41. A product comprising doxepin in anamount of about 0.0001 milligrams to about 0.49 milligrams and writteninformation associated therewith regarding a doxepin food effect.